人生长激素研究进展

综述了人生长激素的结构,及最近几年国内外对人生长激素在分子结构、基因改造、制备、提纯及检测等方面的最新进展和研究趋势,对各种可能影响生长激素分泌的因素进行了分析、讨论。     

The influence of age on human pancreatic growth hormone releasing hormone stimulated growth hormone secretion

63 non-obese healthy subjects aged 18 to 95 years were investigated for age-dependence of GHRH-stimulated GH-secretion. In addition, priming of GH-secretion with three oral doses of propranolol (3 x 80 mg, the last dose 2 hours prior to the second GHRH-bolus) was carried out in 15 subjects below 40 years and 13 subjects older than 70 years. We found that mean maximal incremental GH-levels were inversely correlated with chronological age (r = -0.44, P = 0.001) of the probands. Propranolol premedication caused a significant rise of both basal and peak GHRH-induced relative increases in all subjects tested, whereas GHRH-induced relative increases of GH remained unchanged. In a well selected group of non-obese healthy subjects stimulated GH-secretion is found to undergo an aging process that is supposed to be of pituitary and suprapituitary origin. Priming GH-secretion with a beta-Blocker is possible both in young and very old healthy subjects and is likely to affect the basal GH secretory tone and not GHRH-stimulated GH-secretion.     

Effects of human growth hormone on erythrocyte insulin binding in growth hormone deficient children

In this paper, the effect of acute human growth hormone (GH) administration on erythrocyte insulin binding in GH deficient children (N = 6) was studied. Following GH (0.25 U/kg) administration, the blood levels of GH peaked within 4 to 8 h and returned to basal levels 24 h later. However, the changes in somatomedin activity, free fatty acid (FFA), urea, blood glucose and 125I-insulin binding to erythrocyte were observed around 24 h following the injection, and there was a converse relationship between maximum percent 125I-insulin binding (IBmax) and FFA (P less than 0.02). By Scatchard analysis it was found that the decrease in IBmax is mainly due to the change in the number of insulin receptors. These results suggest that GH may possibly affect the insulin binding to erythrocyte indirectly through metabolic changes as a result of hormonal changes in GH deficient children.     

Effect of human growth hormone on adrenal androgens in children with growth hormone deficiency

The effect of human growth hormone (hGH) on adrenal androgen secretion was assessed in 7 patients (5 males, 2 females) with GH deficiency but normal ACTH-cortisol function. Patients ranged in age from 9 5/12 to 14 8/12 years (median 12 years). Plasma concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and urinary excretion of 17-ketosteroids (17-KS) and free cortisol were determined before, during short-term (2 U/day X 3) and after long-term (6 months) treatment with hGH. No significant change was noted in the plasma concentration or urinary excretion of steroids during the short-term administration of hGH. Despite a significant increase in growth velocity during 6 months of hGH therapy (8.2 vs. 4.5 cm/year, p less than 0.01), the plasma concentrations of DHEA-S and the urinary 17-KS and free cortisol levels were unchanged. These results fail to substantiate a role for hGH in the physiologic control of adrenal androgen secretion. Thus, the low plasma levels of adrenal androgens sometimes seen in GH-deficient patients are not due to the absence of GH per se.     

Effects of human growth hormone on immune functions: in vitro studies on cells of normal and growth hormone-deficient children

We have studied the in vitro effects of human growth hormone on cell surface markers and mitogenic responses of peripheral blood lymphocytes (PBL) of normal and growth hormone-deficient children before, during and after treatment with growth hormone. Growth hormone resulted in a decrease in B cell expression but it did not affect expression of T cell subsets. Growth hormone depressed the proliferation of PBL of normal and untreated growth hormone-deficient children. The proliferative responses to phytohemagglutinin (PHA) versus PHA with growth hormone were not statistically different, though the responses of most normal and on treatment children were diminished by the addition of growth hormone. PBL derived from growth hormone-deficient children during treatment with human growth hormone exhibited significantly greater spontaneous proliferation then the PBL of normal children. Growth hormone further significantly enhanced their proliferation. PHA and PHA with growth hormone resulted in significantly greater proliferation of these patients' PBL when compared to those of normal children. We demonstrated that human growth hormone had substantial in vitro effects on immune functions. These effects, some of which depend on the treatment status of the children, may need to be considered in the clinical use of human growth hormone.     

Induction of specific human growth hormone binding sites in rat liver by human growth hormone.

125I-Labeled hGH was bound to liver plasma membranes which were obtained from female rats. The binding was displaced by hGH, hPRL, bPRL, rPRL and bGH but not by rGH. This result indicated that hGH was bound to lactogenic binding sites in rat livers. After hypophysectomy, the binding was markedly decreased. Treatment of hypophysectomized rats with hGH (80 micrograms/day) for 10 days increased the binding sites for hGH. These binding sites were different from those found in normal female rat livers because of their high affinity and specificity for hGH. These results indicate that hGH induces specific binding sites for hGH in rat livers.     

Computational stabilization of human growth hormone

Recombinant human growth hormone (hGH) is used worldwide for the treatment of pediatric hypopituitary dwarfism and in children suffering from low levels of hGH. It has limited stability in solution, and because of poor oral absorption, is administered by injection, typically several times a week. Development has therefore focused on more stable or sustained-release formulations and alternatives to injectable delivery that would increase bioavailability and make it easier for patients to use. We redesigned hGH computationally to improve its thermostability. A more stable variant of hGH could have improved pharmacokinetics or enhanced shelf-life, or be more amenable to use in alternate delivery systems and formulations. The computational design was performed using a previously developed combinatorial optimization algorithm based on the dead-end elimination theorem. The algorithm uses an empirical free energy function for scoring designed sequences. This function was augmented with a term that accounts for the loss of backbone and side-chain conformational entropy. The weighting factors for this term, the electrostatic interaction term, and the polar hydrogen burial term were optimized by minimizing the number of mutations designed by the algorithm relative to wild-type. Forty-five residues in the core of the protein were selected for optimization with the modified potential function. The proteins designed using the developed scoring function contained six to 10 mutations, showed enhancement in the melting temperature of up to 16 degrees C, and were biologically active in cell proliferation studies. These results show the utility of our free energy function in automated protein design.